We have been studying the interplay between cyclin B-Cdc2 and p42 MAPK (ERX2) in Xenopus oocytes, eggs, and cycling egg extracts. Work from our laboratory and others has shown that p42 MAPK is an important upstream activator of Cdc2 during progesterone-induced oocyte maturation. However, as yet we do not know the identity of the progesterone receptor that triggers p42 MAPK activation and oocyte maturation. p42 MAPK can also act as an inhibitor of Cdc2 activation, a role that appears to be physiologically important during the first embryonic cell cycle. The negative regulation of Cdc2 by p42 MAPK has been hypothesized to be a direct effect of p42 MAPK on Wee1, a negative regulator of Cdc2 that is present in embryos but absent from oocytes. However, the nature of this regulation is poorly understood. Cdc2 can also activate p42 MAPK, and this appears to be important for maintaining the normal timing of mitotic exit in cycling Xenopus egg extracts, and probably in somatic cells as well. The activation of p42 MAPK by Cdc2 depends upon the MEK1 protein, but does not require either of the known upstream activators of MEK1 identified in Xenopus oocytes and eggs (Mos and Raf-1). Here we propose four specific aims:1. To identify the MAPKKK.through which Cdc2 activates p42 MAPK.2. To determine how p42 MAPK negatively regulates Cdc2 during the first mitotic cell cycle.3. To identify the elusive progesterone receptor that initiates oocyte maturation.4. To examine the systems-level properties of a p42 MAPK cascade reconstituted with recombinant Xenopus proteins.Our overarching aim is to better understand the cell biology and biochemistry of oocyte maturation and early embryogenesis.
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